A Comprehensive View Of The Cancer-Immunity Cycle (CIC) in HPV-Mediated Cervical Cancer And Prospects For Emerging Therapeutic Opportunities Part 1

Simple Summary:

Every year, cervical cancer affects more than 500,000 women worldwide. The persistent infection caused by the human papillomavirus (HPV) is the main risk factor for the development of this type of cancer. Conventional treatments for cervical cancer are often associated with resistance and side effects. Therefore, it is necessary to find new targets for the development of more effective therapeutic approaches. In recent years, an increasing number of studies have been concerned with developing immunotherapeutic strategies for treating cancer. 

Cervical cancer is a common malignant tumor in women, and its etiology is complex and related to many factors. In recent years, studies have found that immunity plays an important role in the occurrence and treatment of cervical cancer.

Immunity is an indispensable part of the human life system. It is the basic guarantee for the human body to resist foreign pathogens and maintain life and health. When immunity is compromised, the body is prone to infections, tumors, and other diseases.

Studies have shown that the immune system of patients with cervical cancer decreases, resulting in weakened resistance of the body to viruses and tumor cells, and it is easy to develop cervical cancer. Therefore, improving immunity is very important for the prevention and treatment of cervical cancer.

How to improve immunity? The following points are worthy of attention:

1. A healthy lifestyle, such as proper physical exercise, good sleep, a balanced diet, etc., helps to maintain good health.

2. Cervical cancer vaccination, which can effectively fight viral infection and reduce the risk of cervical cancer. The age of vaccination can start from 9 years old, and it is best to vaccinate before starting sexual life.

3. Regular gynecological examinations, including pap smears, cervical smears, etc., to detect lesions in time and improve the success rate of treatment.

In a word, immunity is one of the important factors to keep healthy. Improving immunity helps to prevent and treat cervical cancer, and is also beneficial to the health of the body. Let us maintain a positive attitude, pay attention to our health, and actively prevent cervical cancer. It can be seen that we need to improve our immunity. Cistanche can significantly improve immunity because the polysaccharides in the meat can regulate the immune response of the human immune system, improve the stress ability of immune cells, and enhance the sterilization of immune cells effect.

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Thus, it is important to investigate new targets, such as the various molecules and cells that are involved in the cancer immunity cycle (CIC). This process consists of the release of cancer antigens and their destruction by cytotoxic T-cells. Hence, in this review, we discuss the molecular changes that occur at each stage of the CIC for cervical cancer, including the impact of variables such as histological subtype and HPV infection. Moreover, we explore the latest immunotherapeutic approaches that have been adopted, together with their benefits and limitations. In this scenario, current studies are opening up new horizons in clinical practice for personalized treatment of cervical cancer.

Abstract:

Cervical cancer (CC) is the fourth most common cancer in women worldwide, with more than 500,000 new cases each year and a mortality rate of around 55%. Over 80% of these deaths occur in developing countries. The most important risk factor for CC is persistent infection by a sexually transmitted virus, the human papillomavirus (HPV). Conventional treatments to eradicate this type of cancer are accompanied by high rates of resistance and a large number of side effects. Hence, it is crucial to devise novel effective therapeutic strategies. In recent years, an increasing number of studies have aimed to develop immunotherapeutic methods for treating cancer. 

However, these strategies have not proven to be effective enough to combat CC. This means there is a need to investigate immune molecular targets. An adaptive immune response against cancer has been described in seven key stages or steps defined as the cancer-immunity cycle (CIC). The CIC begins with the release of antigens by tumor cells and ends with their destruction by cytotoxic T-cells. In this paper, we discuss several molecular alterations found in each stage of the CIC of CC. In addition, we analyze the evidence discovered, the molecular mechanisms and their relationship with variables such as histological subtype and HPV infection, as well as their potential impact for adopting novel immunotherapeutic approaches.

Keywords:

Cervical cancer; HPV; immunotherapy; CIC; molecular targets; ADC; SCC.

1. Introduction

Despite the implementation of human papillomavirus (HPV) vaccination programs, cervical cancer remains one of the main causes of women’s morbidity and mortality worldwide [1,2]. Currently, the conventional protocols to eradicate this type of cancer include hysterectomy, cisplatin-based chemotherapy, and pelvic radiation. However, there is a high recurrence rate among treated women that varies between 17% (in cases of the initial stages of the disease) and up to 74% (in advanced stages) [3]. Thus, the identification of new therapeutic targets for devising novel effective therapeutic strategies is vital.

It is believed that immunotherapy against cancer had its onset as early as 1700 when the beneficial effects that some bacterial infections had on cancer were observed [4]. However, it was not until 1891 that the surgeon William B. Coley began to treat patients suffering from inoperable cancers with streptococcal injections and obtained healing and sustained remission in up to 10% of cases [4,5]. 

Nonetheless, the emergence of chemotherapy and radiotherapy created some skepticism about this type of treatment, and the practice was abandoned for a long time. Only in the 1990s did the immunologists James Patrick Allison and Tasuku Honjo resume this idea and they were awarded the Nobel Prize for Medicine in 2018 for identifying the Cytotoxic T-lymphocyte-associated protein (CTLA) 4 and programmed cell death protein (PD) 1, as well as for their role in the negative regulation of the immune response to cancer [6,7]. Since then, several different researchers have decided to study the mechanisms involved in the antitumor immune response.

Cytotoxic CD8+ T-cells have been identified as the preferred target of study for cancer immunotherapy because when there is a decrease in their activity, this is significantly linked to a failure of the antitumor immune response system [8,9]. However, other T-cell subtypes are also important; for example, CD4+ T-cells are crucial because they help to potentiate the cytotoxic activity of CD8+ T-cells [10]. 

Additionally, regulatory T-cells (Tregs), which normally represent only a small percentage of T-cells, have their number increased in cancer and their immunotolerogenic functions have been shown to have a close association with recurrence, tumor progression, and resistance to treatment [11]. Furthermore, the current findings indicate that both innate immunity and adaptive cellular and humoral immunity are required for an effective immune response against cancer [12–16]. 

Although it is widely recognized that an integrated immune response system is necessary for the development of therapies that lead to the detection and destruction of tumor cells, most research has been focused on studying adaptive cellular immunity (ACI) because of its specificity and immunological memory induction [17–21].

Studies of ACI against cancer have led to the description of the “Cancer-Immunity Cycle” (CIC), which consists of seven key stages beginning from the release of antigens by tumor cells to their destruction by cytotoxic T-cells. Although this process can be divided into stages, it should be noted that it is cyclical, highly integrated, and interdependent. Likewise, as will be addressed later, several molecular mechanisms have been found in each step, which compromise the efficient immune response against cervical cancer, and for this reason, several strategies have been adopted for the development of vaccines or the use of targeted therapies [17–21].

2. Molecular Events in the Cancer-Immunity Cycle and Development of Cervical Tumors

The CIC consists of seven main phases or stages: during the first stage, there is a release of antigens caused by the death of tumor cells; in the second, antigen recognition and processing takes place; in the third, the antigen-presenting cells prime and activate naive T-cells; in the fourth, the primed T-cells migrate to the tumor; in the fifth, the T-cells infiltrate the tumor tissue; in the sixth, T-cells are recruited, and recognize the tumor cells; and finally, in the seventh step, cytotoxic cells destroy the cancer cells (Figure 1) [17–21].

It has been established that some events that are induced by HPV oncogenes are required for the development of cervical cancer [22]. One such event is the modulation of the host’s immune response to prevent and control infection. At the same time, since HPV allows the panel of immunologic molecules to persist in the epithelium, the virus might give rise to a tumor microenvironment [23]. The tumor microenvironment (TME) is a complex mixture of malignant and nonmalignant cells and surrounding elements that interact with each other to induce cancer progression and the development of the malignant phenotype. The main non-cancerous features of the TME include the extracellular matrix (ECM), blood vessels, immune cells, stromal cells, the presence of oxygen, and nutrient levels. All these factors are favorable to tumors and their progressive growth, and they particularly influence the following situations: (a) when a tumor escapes immune surveillance, (b) the activation of angiogenesis, and (c) cell proliferation, invasion, and metastasis [24]. For instance, the growth of new blood vessels (angiogenesis), which is regarded as a hallmark of cancer, provides the oxygen and nutrients that are required for tumor development [25,26]. In addition, immune cells such as B-cells, T-cells, macrophages, and dendritic cells can alter the behavioral patterns of cancer cells and affect the tumoral immune milieu [27]. The immune system plays a crucial role in the control of persistent infection of HPV, and the TME can contain immune cells that actively suppress the immune response system by allowing the cancer to evade the immune system [28,29]. 

The TME in cervical cancer can be characterized as an HPV infection associated with chronic inflammation, which leads to the accumulation of immune cells, such as T-cells and macrophages; this can cause inflammation and oxidative stress in the TME [30–34]. Additionally, the presence of regulatory T-cells (Tregs), tumor-associated macrophages (TAM) of the M2 phenotype, and cancer-associated fibroblasts (CAFs) generate an immunosuppressive TME, which has been attributed to a poor prognosis of various types of cancer [35,36], such as cervical cancer [37,38]. 

However, several studies have demonstrated that factors secreted by cervical cancer cells induced a stable M2 phenotype in macrophages. Macrophages of the M2 phenotype lead to the Th2 immune response, and the development of tumors through the expression of the vascular endothelial growth factor (VEGF) (which suppresses pro-inflammatory Th1 and cytotoxic lymphocyte responses), as well as the transforming growth factor (TGF)-b, indoleamine 2,3-dioxygenase, and programmed death ligand 1 expression [39,40]. 

Several reports have described the secretion of various factors, including IL-6, IL-13, TGF-b, VEGF, and prostaglandin E2 by CxCa cells [11,17–19]. However, it has not yet been established whether the factors secreted by CxCa cells play a key role in the induction or maintenance of the M2 macrophage phenotype. Moreover, fibroblasts and smooth muscle cells, which form a part of the stromal cell structure, interact with the cancer cells and assist in shaping the physical and biological microenvironment of the tumor [41]. 

In vitro studies have shown that cervical cancer-associated fibroblasts might play a role in the proliferation and survival of tumoral cells [42,43], as well as in ECM remodeling [44].

Furthermore, it has been found that alterations in the bacterial diversity of the female genital tract occur in CC. These alterations might include an increase in the abundance of certain bacteria, such as Gardnerella vaginalis and Lactobacillus acidophilus, and a reduction in the abundance of beneficial bacteria, such as L. iners, L. crispatus, and L. taiwanensis [45]. The exact mechanisms through which these changes in bacterial diversity can lead to the development of cervical cancer are not yet fully understood, but it is believed that the changes in the microbiome might affect the local immune response system and result in the development of precancerous lesions. Further research is needed to fully understand the specific alterations in bacterial diversity and their role in cervical cancer. The different features of the microenvironment may interact and have a reciprocal effect on each other, thus creating an uncertain and evolving ecosystem that contributes to the progression of HPV-related CC. Thus, understanding the TME and its interactions is essential for developing new therapeutic strategies and for improving disease prognosis. As a result, HPV also interferes with the CIC and leads to a more complex process of cancer progression which arises from an interaction between the virus, immune system, and tumor microenvironment.

The following sections will describe the CIC in cervical cancer, from an integrated standpoint by investigating the alterations in each stage and their relationship with the histological subtype of cervical cancer and HPV infection. Additionally, it should be noted that our main focus will be on cervical squamous cell carcinoma (CSCC) and cervical adenocarcinoma (ADC), which are the two main types of cervical cancer that originate from the squamous epithelium and glandular epithelium of the cervix, respectively.

2.1. Cell Death and Antigen Release (Step 1)

Several studies have found key changes in the gene expression involved in the mechanisms of programmed cell death or apoptosis in cervical cancer [46]. From an immunological standpoint, this has subsequently led to a decrease in the release of antigens, which are later recognized by the immune system. Some of the key changes include collagen type alpha 1 (COL1A1) upregulation and phosphotyrosine phospho-histidine inorganic pyrophosphate phosphatase (LHPP) downregulation. This perturbation is related to the reduction in Caspase 3 and BCL.2-associated X (Bax) pro-apoptotic proteins and the increase in B cell lymphoma 2 (Bcl-2) anti-apoptotic protein [47 49]. 

Additionally, apoptosis-stimulating protein 2 (ASPP2) has been found downregulated in CC cells, decreasing apoptosis by the regulation of autophagy mechanisms [49,50]. Among other alterations inhibiting apoptosis, it has been observed that fibronectin 1 (FN1) impedes the apoptosis of cancer cells and increases their migratory capacity and invasion through the focal protein adhesion kinase (FAK) signaling pathway [51]. Likewise, human hydroxysteroid dehydrogenase-like2(HSDL.2) upregulation, which participates in fatty acid metabolism regulation, suppresses apoptosis by an unrevealed mechanism in Hela, C33A, and SiHa cells (52,53).

Similarly, there has also been evidence of changes in the expression of long noncoding RNAs (lncRNAs) and microRNAs (miRNAs), as associated with tumor growth stimulation and the inhibition of apoptosis. For instance, lncRNA F-box and leucine-rich repeat protein 19 antisense RNA 1 (FBXL19-AS1) upregulation increase the capture of miR-193a-5p, stimulating COL1A1 expression [48]. 

This gene is linked to a reduction in the pro-apoptotic Bcl-2 protein. Similarly, the induction of two lncRNAs MEG3 (maternally expressed gene 3) and HAND2-AS1 (heart and neural crest derivatives expressed 2-antisense RNA 1), both downregulated in CC, decreases miR-21-5p expression (upregulated in CC), decreases cell proliferation, and increases the apoptosis of CC cells [54–56]. A miRNA that is downregulated in CC is the miR-433, which is associated with the apoptosis key regulator p53. Then, it was observed that miR-433 upregulation, using in vitro models, upregulates p53 and Bax genes and downregulates murine double minute 2 (MDM2); it also increased the activity of Caspases 3 and 9 and, hence, the apoptosis of tumor cells [57]. 

Moreover, miR-433 interacts with messenger RNA (mRNA) coding the FAK protein in such a way that the decrease of miR-433 upregulates FAK, PI3K, and p-Akt by inhibiting cell death [57]. Other non-coding RNAs, such as the lncRNA CCAT-1(colon cancer-associated transcript-1 gene), miR-182, and miR-26a-5p have been associated with augmented cell proliferation and reduced apoptosis of CC cells by mechanisms not yet uncovered [52,53,58–60]. It has already been shown that HPV oncoproteins can modulate the expression of protein-coding genes and non-coding RNA genes to promote cervical carcinogenesis [22]. However, it is presently unknown if there is a role of HPV infection in the alterations of those molecules mentioned above, such as the non-coding RNAs. More research is needed to clarify the molecular mechanisms that are involved.

On the other hand, it is well known that E6 and E7 HPV oncoproteins impair the apoptosis process and hence the release of antigens by targeting cellular factors and certain molecules involved in the activation of apoptosis, such as the following: the p53 tumor suppressor protein [61], the tumor necrosis factor (TNF), and the TNF-related apoptosis-inducing ligand (TRAIL) [62]; the miR-21 and the miR-27b, targeting the TNF-alpha and polo-like kinase 2 (PLK2), respectively, to suppress apoptosis [63,64]; and the lncRNA CRNDE, involved in cell survival through the p53 pathway [65,66].

Despite defective apoptosis being associated with the impairment of the immune response because of less available amounts of antigens to be presented to immune cells, this statement needs to be analyzed carefully. Currently, evidence suggests that apoptosis may act as an immunosuppressive or an immunostimulatory signal. Therefore, variables such as stages and the mechanisms involved in apoptosis activation and microenvironment stimuli should be considered [67].

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